GdIII complexes with fast water exchange and high thermodynamic stability:: Potential building blocks for high-relaxivity MRI contrast agents

On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd-III poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA(5-)ligand (DTPA = (diethylenetriamine-N,N,N',N",N"-pentaacetic acid) by replacing one (EPTPA(5-)) or two (DPTPA(5-)) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop(5-)). The ligand EPTPA(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO25-) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable-temperature O-17 NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa-bz-NO2)(H2O)](2-) and [Gd(eptpa)(H2O)](2-) than on [Gd(dtpa)(H2O)](2-) (k(ex)(298) 150 x 10(6), 330 x 10(6), and 3.3 x 10(6) s(-1), respectively). This is optimal for attaining maximum proton relaxivities for Gd-III-based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable-pressure O-17 NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H2O)](2-) (DeltaVdouble dagger = (+6.6 +/- 1.0)cm(3)mol(-1)). In contrast to [Gd(eptpa)(H2O)](2-), an interchange mechanism is proved for the macrocyclic [Gd(trita)(H2O)](-) (DeltaV(double dagger) = (- 1.5 +/- 1.0) cm(3) mol(-1)), which has one more CH2 group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H2O)(-), and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA(5-) substituted by a propionate, the water exchange rate on the Gdln complex increases by a factor of 10 k(ex)(298) = 31 x ex 10(6) s(-1)). The [Gd(dptpa)](2-) chelate has no inner-sphere water molecule. The protonation constants of the EPTPAbz-NO2 (5-) and DPTPA(5-) ligands and the stability constants of their complexes with Gd-III, Zn-II, Cut(II) and Call were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa-bz-NO2)(H2O)](2-) is reduced to a slight extent in comparison with [Gd(dtpa)(H2O)](2-), it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate(-) and [Gd(trita)(H2O)](-) are potential building blocks for the development of high-relaxivity macromolecular agents.